POT1 loss-of-function variants predispose to familial melanoma.
POT1 loss-of-function variants predispose to familial melanoma.
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DOI：
10.1038/ng.2947
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发表时间：
2014-05
期刊：
影响因子：
30.8
通讯作者：
Adams DJ
中科院分区：
文献类型：
--
作者：
Robles-Espinoza CD;Harland M;Ramsay AJ;Aoude LG;Quesada V;Ding Z;Pooley KA;Pritchard AL;Tiffen JC;Petljak M;Palmer JM;Symmons J;Johansson P;Stark MS;Gartside MG;Snowden H;Montgomery GW;Martin NG;Liu JZ;Choi J;Makowski M;Brown KM;Dunning AM;Keane TM;López-Otín C;Gruis NA;Hayward NK;Bishop DT;Newton-Bishop JA;Adams DJ
CDKN 2A中的有害种系变异占家族性黑色素瘤病例的40%左右，而CDK 4，BRCA 2，BAP 1和TERT启动子中的罕见变异也与该疾病有关。在这里，我们通过对来自英国、荷兰和澳大利亚的105个家系的184名黑色素瘤患者进行测序，确定了不明原因病例中新的高突变易感基因。我们确定了黑色素瘤与端粒1（POT 1）基因保护功能丧失变体共分离的家族，其中一部分成员表现为早期发病和多原发。我们发现，这些变体影响POT 1 mRNA剪接或改变POT 1的高度保守的寡核苷酸/寡糖结合（OB）结构域中的关键残基，破坏蛋白质-端粒结合，导致端粒长度增加。因此，POT 1变体通过对端粒的直接作用而易于形成黑色素瘤。
Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases, while rare variants in CDK4, BRCA2, BAP1, and the promoter of TERT, have also been linked to the disease. Here we set out to identify novel high-penetrance susceptibility genes in unexplained cases by sequencing 184 melanoma patients from 105 pedigrees recruited in the United Kingdom, the Netherlands, and Australia that were negative for variants in known predisposition genes. We identify families where melanoma co-segregates with loss-of-function variants in the protection of telomeres 1 (POT1) gene, a proportion of members presenting with an early age of onset and multiple primaries. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide-/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding, leading to increased telomere length. Thus, POT1 variants predispose to melanoma formation via a direct effect on telomeres.
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影响因子：
30.8
作者：
Wiesner, Thomas;Obenauf, Anna C.;Murali, Rajmohan;Fried, Isabella;Griewank, Klaus G.;Ulz, Peter;Windpassinger, Christian;Wackernagel, Werner;Loy, Shea;Wolf, Ingrid;Viale, Agnes;Lash, Alex E.;Pirun, Mono;Socci, Nicholas D.;Ruetten, Arno;Palmedo, Gabriele;Abramson, David;Offit, Kenneth;Ott, Arthur;Becker, Juergen C.;Cerroni, Lorenzo;Kutzner, Heinz;Bastian, Boris C.;Speicher, Michael R.
通讯作者：
Speicher, Michael R.
影响因子：
48
作者：
Gonzalez-Perez A;Perez-Llamas C;Deu-Pons J;Tamborero D;Schroeder MP;Jene-Sanz A;Santos A;Lopez-Bigas N
通讯作者：
Lopez-Bigas N
影响因子：
6.5
作者：
Law, Matthew H.;MacGregor, Stuart;Hayward, Nicholas K.
通讯作者：
Hayward, Nicholas K.
影响因子：
1.8
作者：
Lopes MC;Joyce C;Ritchie GR;John SL;Cunningham F;Asimit J;Zeggini E
通讯作者：
Zeggini E
影响因子：
14.9
作者：
Ding Z;Mangino M;Aviv A;Spector T;Durbin R;UK10K Consortium
通讯作者：
UK10K Consortium